This transformative research proposal extends from my discovery that embryonic lethality in caspase 8 (Casp8)-deficient mice the result of unleashed RIP3 necrosis. Casp8-/-Rip3-/- mice develop into viable, fertile and immunocompetent adults that retain positive innate signaling through NF-kappaB and other factors, but lack detrimental apoptosis and necrosis pathways associated with inflammatory disease, autoimmunity and oncogenesis, prompting the question, What benefit(s) comes from life in the absence of extrinsic cell death pathways and how can this be harnessed in the clinic? The developmental dysregulation suggested benefits might be gained in areas as diverse as tissue engraftment and nuclear reprogramming. Surprisingly, Casp8-/- Rip3-/- mice are immunocompetent but tolerate engraftment with mismatched bone marrow. Casp8-/-Rip3-/- cells support nuclear reprogramming with dramatically improved efficiency. In addition, Casp8-/-Rip3-/- mice exhibit resistance to inflammatory cancer. The Challenge is to retain positive mechanisms of innate signaling and eliminate deleterious consequences of dysregulation through genetic manipulation, and then to translate these findings into therapeutic interventions that improve tissue repair and regeneration. We propose to investigate genetic deficiency together with small molecule inhibitors of Casp8 protease and RIP3 kinase to improve tissue transplantation and nuclear reprogramming. The Innovation has begun to emerge. Inflammatory disease and ischemia-reperfusion damage is reduced and allograft transplantation is dramatically improved in the absence of Casp8 and RIP3 kinase. Casp8-/-Rip3-/- mice fail to respond to inflammatory insult sufficient to kill WT mice. Fibroblasts from these mice reprogram into induced pluripotent stem cells (iPSCs) with dramatically improved efficiencies. Additional high impact findings will emerge with genetic knock-out mice as well as with small molecule inhibitor, improving reprogramming of mouse, rhesus and human fibroblasts to iPSCs and/or therapeutically important somatic cell progenitors. The Impact will come from existing and expected innovations, ranging from genetic elimination detrimental cell death in mice, to the use of powerful genetic and therapeutic strategies on rhesus and human cells. Through parallel genetic and small molecule therapeutic intervention, this knowledge will move towards practical clinical applications, with the important involvement of expert consultants in these medically relevant areas. Starting with mouse models, I will: (1) improve tissue regeneration, (2) optimize allogeneic engraftment, and (3) enhance nuclear reprogramming, establishing a new paradigm by eliminating extrinsic apoptosis without the disadvantage of triggering necrosis. The knowledge gained through these studies will be transformative in current tissue repair and transplantation approaches, and will revolutionize future regenerative medicine strategies.